Synthesis and biological evaluation of 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones

Article abstract of DOI:10.1016/j.bmcl.2019.05.001

A series of novel, substituted 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones have been prepared and shown to exhibit promising concentration-dependent activity against human SH-SY5Y cells, Plasmodium falciparum, Mycobacterium tuberculosis and P. aeruginosa. Substituent effects on observed bioactivity have been explored; the para-fluorophenyl derivative 3d exhibited activity across the range of the bioassays employed, indicating the potential of the 2-chloro-3-[(4-arylthiazol-2-yl)amino]-1,4-naphthoquinone scaffold in the development of novel, broad spectrum therapeutics.

Full text of DOI:10.1016/j.bmcl.2019.05.001

Accepted Manuscript
Synthesis and Biological Evaluation of 2-Chloro-3-[(thiazol-2-yl)amino]-1,4-
naphthoquinones
Emmanuel O. Olawode, Roman Tandlich, Earl Prinsloo, Michelle Isaacs,
Heinrich Hoppe, Ronnett Seldon, Digby F. Warner, Vanessa Steenkamp, Perry
T. Kaye
PII:
S0960-894X(19)30287-2
https://doi.org/10.1016/j.bmcl.2019.05.001
BMCL 26421
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 March 2019
30 April 2019
2 May 2019
Please cite this article as: Olawode, E.O., Tandlich, R., Prinsloo, E., Isaacs, M., Hoppe, H., Seldon, R., Warner,
D.F., Steenkamp, V., Kaye, P.T., Synthesis and Biological Evaluation of 2-Chloro-3-[(thiazol-2-yl)amino]-1,4-
naphthoquinones, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.
2019.05.001
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Synthesis and Biological Evaluation of 2-Chloro-3-
[(thiazol-2-yl)amino]-1,4-naphthoquinones
Emmanuel O. Olawode,a*† Roman Tandlich,a Earl Prinsloo,b Michelle Isaacs,c Heinrich Hoppe,c,d
Ronnett Seldon,e Digby F. Warner,f Vanessa Steenkamp,g Perry T. Kayed,h*
aDivision of Pharmaceutical Chemistry, Faculty of Pharmacy Rhodes University, Grahamstown 6140, South Africa.
bDepartment of Biotechnology, Rhodes University, Grahamstown 6140, South Africa.
cDepartment of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
dCentre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
eDrug Discovery and Development Centre (H3-D), Department of Chemistry, University of Cape Town, Rondebosch
7701, South Africa
fMolecular Mycobacteriology Research Unit, Department of Pathology and Institute of Infectious Disease and Molecular
Medicine, University of Cape Town, Cape Town, South Africa.
gDepartment of Pharmacology, University of Pretoria, Pretoria, South Africa
hDepartment of Chemistry, Rhodes University, Grahamstown 6140, South Africa.
Abstract. A series of novel, substituted 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones have
been prepared and shown to exhibit promising concentration-dependent activity against human SH-
SY5Y cells, Plasmodium falciparum, Mycobacterium tuberculosis and P. aeruginosa. Substituent
effects on observed bioactivity have been explored; the para-fluorophenyl derivative 3d exhibited
activity across the range of the bioassays employed, indicating the potential of the 2-chloro-3-[(4-
arylthiazol-2-yl)amino]-1,4-naphthoquinone scaffold in the development of novel, broad spectrum
therapeutics.
Keywords. 2-Chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones, anti-malarial, anti-bacterial, anti-
tuberculosis, cytotoxicity, HeLa cells
*Corresponding authors: Dr E.O. Olawode. E-mail: eolawode@binghamton.edu and
Prof P.T. Kaye. Tel.: +27 46 6038268; fax: +27 46 6225109. E-mail: P.Kaye@ru.ac.za.
†Current address: School of Pharmacy and Pharmaceutical Sciences, Binghamton University, 96
Corliss Avenue, Johnson City 13790, New York, U.S.A.
1

Compounds containing the 1,4-naphthoquinone moiety are commonly found in antibiotics isolated
from marine microorganisms, particularly bacteria and sponges.1-7 These compounds have been
reported to exhibit wide-ranging pharmacological properties including antimicrobial,1,2,8-12 anti-
cancer,2,3,13-15 antiviral,16 trypanocidal,17 antifungal,18 antiparasitic,19 antimalarial20 and
antimycobacterial21 activity. The main mechanism for the pharmacological action of 1,4-
naphthoquinone derivatives depends on their capacity to form radicals in vivo, especially via the
metabolic effects of the cytochrome P450 enzyme complex in the liver.22 This may explain the anti-
oxidant, anti-cancer and anti-diabetic activities exhibited by various 1,4-naphthoquinone derivatives.
Nicotinamide adenosine diphosphate (NADP), or its reductive analogue, NADPH-dependent
quinone oxidoreductase (NQO1),15,23,24 are key targets in the design and development of quinone-
25
based anti-cancer agentsThe 5,8-quinolinedione analogues, streptonigrin 1 and lavendamycin,26
have been shown to inhibit the latter enzyme.
Pettit et al.2 reported the anti-cancer activity of cribrostatin 2 against various cancer cell lines,
including pancreas-adenocarcinoma BXPC-3, breast-adenocarcinoma MCF-7, CNS glioblastoma
SF-268, lung-NSC NCI-H460, colon-adenocarcinoma KM20L2, prostate DU-145 and mouse
leukemia P388; the GI50 values were mostly in the 0.21-1 µg/mL range. Atamanyuk et al.27
evaluated the anti-neoplastic and anti-mycobacterial potential of 1,4-naphthoquinone-derived 3,11-
dihydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]-thiazole-2,5,10-triones, while Cai et al.8 reported
the total synthesis of hygrocin A and B, which contain the 1,4-naphthoquinone motif and exhibit
moderate antibacterial activity against Neisseria gonorrheae (a Gram-negative bacterium) and
Aspergillus fumigates (a fungus). Stasevych et al.28 have used disc-diffusion susceptibility
antimicrobial assays to demonstrate the capacity of certain 2-substituted-3-mercapto-1,4-
naphthoquinones to selectively inhibit either Escherichia coli (Gram-negative) or Staphylococcus
aureus (Gram-positive) bacteria.
In this communication, we report the preparation and biological evaluation of a series of 1,4-
naphthoquinone-derived 3-(thiazolylamino)naphthoquinones 3a-g as potential multifunctional anti-
cancer, anti-mycobacterial and anti-malarial agents.
O
O
O
O
O
O
H
N
MeO
H2N
OMe
N
NH2
R
N
S
2
N
OMe EtO
Cl
N
OH
N
1
2
3
CO2H

The preparation of the known 2-aminothiazoles 6a-f,9-11 required as precursors for the targeted 2-
chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones 3a-f, was accomplished by conventional
Hantzsch condensation of thiourea 4 with the α-haloketones 5a-f (Scheme 1). After completion of
each reaction, the reaction mixture was poured into ice-cold water to precipitate the thiazole
derivatives 6a-f in excellent yields (93–100%). With the precursors in hand, studies were undertaken
to optimise reaction conditions for the synthesis of the targeted compounds (3). These included the
use of: i) different solvents [viz., polar protic solvents (EtOH and MeOH), non-polar aprotic solvents
(THF, toluene and methylene chloride) and protic apolar solvents (DMSO and DMF)]; ii) different
o
bases (triethylamine, pyridine or K2CO3); iii) different temperatures (ambient to 110 C); iv)
different reaction times (1-48 hours); and v) microwave-assisted conditions with or without solvent
o
at 150 C for 10 minutes. Successful nucleophilic displacement of one of the chlorine atoms in 2,3-
dichloro-1,4-naphthoquinone 7 by each of the 2-aminothiazoles 6a-f was finally achieved using
DMF in the presence of K2CO3 to obtain, without heating, the desired 2-chloro-3-[(thiazol-2-
yl)amino]-1,4-naphthoquinones 3a-f. All of the compounds were fully characterised using 1- and 2-
D NMR, IR and HRMS methods; the ‘parent’ system 3a12,17 is known but the analogues 3b-g are
new compounds. Although overall substitution of chloride by the nucleophilic 2-aminothiazole is
achieved in these reactions, the proposed mechanism involves conjugate-addition followed by
elimination of HCl.12,29 The 3-[(4-carbethoxythiazol-2-yl)amino]-2-chloro-1,4-naphthoquinone 3f
was hydrolysed in methanolic KOH to give the corresponding acid 3g in moderate yield (53%).
Experimental details and characterisation data for all of the compounds synthesised in this study are
provided in the Supplementary Data file.
3

S
O
O
H2N
NH2
NH2
EtOH,
Cl
Cl
N
4
R
S
O
70 o C, 1h
Br
6a-f
7
R
5a-f
Yield (%)
K2CO3,
DMF,
R
rt, 5 h.
Ph
p-ClPh
6a
6b
99
100
93
3a
3b
70
61
O
O
p-BrPh
p-FPh
6c
6d
6e
3c
3d
3e
51
57
73
H
N
N
94
R
p-NO2Ph
94
S
Cl
COOEt
COOH
6f
-
100
-
3f
3g*
54
57
3a-g*
Scheme 1. Synthesis of 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones.
* Compound 3g obtained by subsequent hydrolysis of 3f.
The cytotoxic activity of compounds 3a-g were examined in two cancer cell lines, viz., HeLa cervical
adenocarcinoma and SH-SY5Y neuroblastoma cells. The SH-SY5Y cells showed a dose-dependent
response to the compounds, with higher concentrations (particularly at 100 μM) inhibiting the
growth of the cells, while lower concentrations showed similar effects to the untreated SH-SY5Y
control. The xCELLigence RTCA-SP scans of the effects of different concentrations of compound
3d on SH-SY5Y cells (Figure 1) are typical of the series of compounds examined. At lower
concentrations (100 nM-1 µM), this compound (3d) resulted in similar patterns of growth to that
observed with the untreated control, but at higher concentrations (10-100 μM) inhibited the growth
of the cells at levels comparable to the negative control (i.e., media without the test sample). The
carboxylic acid 3g and the precursor ester 3f exhibited the lowest inhibitions with IC50 values > 100
μM and 31.1 μM, respectively (Table 1). The phenyl-substituted analogues, however, exhibited
significant cytotoxicity, with the unsubstituted phenyl (3a), para-chlorophenyl (3b), para-
fluorophenyl (3d) and para-nitrophenyl (3e) derivatives exhibiting IC50 values of 1.8, 2.7, 1.5 and
0.004 μM, respectively. These results suggest that the presence of the phenyl substituent and its
electronegative para-substituents, particularly p-NO2, may increase the binding affinity of these
compounds to the binding pocket of the SH-SY5Y cells.
4

In contrast, compounds 3a-g exhibited relatively low cytotoxicity against the HeLa cell line at a
concentration of 20 µM (Table 1), indicating selective inhibition of SH-SY5Y cells by the phenyl-
substituted compounds 3a-e. Further studies are required to determine the mechanism of action of
these compounds and their morphological effects on both cell lines.
Figure 1. Scans of Cell Index (CI) of SH-SY5Y vs time (h) for different concentrations of 2-chloro-
3-[4-(4-fluorophenyl)thiazol-2-ylamino]-1,4-naphthoquinone 3d over 48 h using an xCELLigence
RTCA-SP instrument.
The results of the anti-TB bioassay of the 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones 3a-
g against the virulent M. tuberculosis H37Rv strain are presented in Table 1 (dose-response curve are
provided in the Supporting Information file). While the carboxylic acid (3g) and ester (3f)
derivatives exhibited low levels of anti-TB activity, with MIC90 and MIC99 values > 20 µM, certain
phenyl derivatives showed promising anti-TB activities with MIC90 and MIC99 values < 10 µM (3a:
MIC90 = 9.19 µM and MIC99 = 10.2 µM); 3d: MIC90 = 9.39 µM and MIC99 = 10.4 µM). All of the
naphthoquinone derivatives (3) were found to have favourable (<5) Log P values, but the predicted
aqueous solubilities (0.15 mg/mL and 0.08 mg/mL) of compounds 3a and 3d, respectively, were
significantly higher than those of their aryl-substituted analogues 3b, 3c and 3f which may
enhancetheir absorption across the mycolic-rich lipophilic cell wall of M. tuberculosis.
5

Whole-cell PfLDH bioassays were conducted to determine the antimalarial activities of the 2-chloro-
3-[(thiazol-2-yl)amino]-1,4-naphthoquinones 3a-g, using 20 µM as the baseline concentration before
determining IC50 values for compounds with significant levels of inhibition. Chloroquine was used as
the positive control. The results showed that the ‘parent’ compound 3a, and the p-chlorophenyl (3b)
and ethyl ester (3f) analogues exhibited low levels of inhibition against P. falciparum at the tested
concentration, with values of 10%, 30% and 40% respectively, while analogues 3c-e exhibited 80-
90% inhibition of parasite viability at the tested concentration; IC50 values of 50.6, 44.7 and 20.3 µM
were determined for the latter compounds, 3c, 3d and 3e respectively (Table 1). The acid derivative
3g, on the other hand, enhanced the growth P. falciparum, recording 115% viability of the cells.
Graphs showing the IC50 plots and the % parasite viabilities with related standard deviations are
provided in the Supplementary Data file. The results clearly reveal the importance of the thiazole
substituent.
i) The acyl derivatives are clearly the least promising, with the ethyl ester 3f exhibiting the
lowest inhibition (10%) and its carboxylic acid derivative 3g actually stimulating
proliferation of P. falciparum by 15%
ii) Compared to the ‘parent’ system 3a (R = Ph), the introduction of the electronegative para-
substituents Br, F and NO2 in the phenyl group in compounds 3c, 3d and 3e, respectively,
appears to decrease the viability of the parasite significantly.
The results of the disc diffusion susceptibility studies of the 2-chloro-3-[(thiazol-2-yl)amino]-1,4-
naphthoquinones 3a-g against an environmental strain of P. aeruginosa are summarised in Table 1.
As was the case with the antimalarial bioassays, neither the carboxylic acid 3g nor the ester precursor
3f showed any inhibition potential, even at the highest concentration (2000 µM). The phenyl
derivatives 3a,b,d,e, on the other hand, exhibited dose-dependent antibacterial activity, with the
para-fluorophenyl derivative 3d exhibiting the highest inhibition across the different concentrations
tested by clearing zones of 5 mm, 8 mm, 11 mm, 15 mm and 19.5 mm at 1 µM, 10 µM, 100 µM,
1000 µM and 2000 µM, respectively.
A series of 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones derivatives 3a-g have thus been
successfully synthesised in moderate to good yield (51–73%). Various compounds exhibited
concentration-dependent activities in each of the biological studies. The presence of the phenyl ring,
6

particularly when bearing electronegative para-substitutuents, clearly increases the levels of
antimalarial and antibacterial activity, with the para-fluorophenyl derivative 3d proving to be
consistently active across all of the bioassays. These results indicate the potential of the title
compounds 3a-e to serve as lead compounds in the development of novel, multifunctional
therapeutics.
7

Table 1. Biological evaluation of the 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones 3a-g.
O
H
N
N
R
S
Cl
O
R
Cytotoxicity
SH-SY5Y HeLa
Anti-TB
MIC99
Antimalarial
Antimicrobial
MIC90
% Viabilitya (µM)
PfLDH
IC50 (μM)
Zone of inhibition (mm)
IC50 (µM)
(µM)
2000 µM 1000 µM
100 µM 10 µM 1 µM
9.19b
> 20.0
> 20.0
9.37b
> 20.0
19.5
> 20.0
10.2b
> 20.0
> 20.0
10.4b
> 20.0
> 20.0
> 20.0
3a
3b
3c
3d
3e
3f
Ph
p-ClPh
p-BrPh
p-PhF
p-NO2Ph
COOEt
COOH
1.8
2.7
-
-
-
13.2+0.6
12+0.7
11.4+0.9
9.7+0.5
9.1+0.4
7.6+1
5.3+0.5
-
-
-
-
80+5.9
80+2.1
55+1.8
75+2.6
80+3.6
82+2.8
75+1.8
50.6
44.7
20.3
-
-
-
-
-
1.5
19.5+0.5
14.10+0.8
15+0.4
11+013
11+0.6
7.2+0.7
8+0.7
5+0.3
0.004
31.1
> 100
-
-
-
-
-
-
-
-
-
-
-
-
3g
-
Controls
Chloroquine
Rifampicin
Ampicillin (25 μg/disc) -
-
-
3.6+0.1
-
-
0.0143
-
-
-
-
-
-
-
-
0.0015
0.00167
-
-
-
-
-
-
-
24.7+1.2
20.0+0.8
Streptomycin (10 μg/disc) -
a At 20 µM. b MIC values approximately 10 µM or lower.
8

Acknowledgments
The authors wish to thank Rhodes University for bursary support (to E.O.O.) and the South
African Medical Research Council (SAMRC) and Rhodes University for research funding.
Supplementary data
Supplementary data associated with this article can be found in the online version.
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NH2
N
R
S
O
6a-f
H
N
N
O
R
Cl
S
Cl
O
3a-f
Cl
O
7
3e
IC50 values for
(R=NO2):
4 nM (SH-SY5Y); 20.3 M (PfLDH)
12